rs3217986

Variant names:

• chr9-22005331-T-G
• rs3217986
• NM_004936.4:c.*656A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004936.4(CDKN2B):​c.*656A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0877 in 238,184 control chromosomes in the GnomAD database, including 1,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.087 (966 hom., cov: 32)
  • Exomes 𝑓: 0.089 (484 hom.)
• Consequence: CDKN2B NM_004936.4 3_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.659
• Publications: 44 publications found

Genes affected

CDKN2B (HGNC:1788): (cyclin dependent kinase inhibitor 2B) This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, Jul 2008]

CDKN2B-AS1 (HGNC:34341): (CDKN2B antisense RNA 1) This gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. The gene product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma. Multiple alternatively processed transcript variants have been detected, some of which may take the form of circular RNA molecules (PMID:21151960). [provided by RefSeq, May 2014]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2B	NM_004936.4	c.*656A>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000276925.7	NP_004927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2B	ENST00000276925.7	c.*656A>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_004936.4	ENSP00000276925.6

Frequencies

GnomAD3 genomes AF: 0.0867 AC: 13188 AN: 152054 Hom.: 968 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0901

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0856

Gnomad OTH AF: 0.0915

GnomAD4 exome AF: 0.0894 AC: 7689 AN: 86012 Hom.: 484 Cov.: 0 AF XY: 0.0888 AC XY: 3523 AN XY: 39688

African (AFR) AF: 0.0173 AC: 68 AN: 3924

American (AMR) AF: 0.298 AC: 1060 AN: 3562

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 448 AN: 5152

East Asian (EAS) AF: 0.0591 AC: 681 AN: 11532

South Asian (SAS) AF: 0.161 AC: 161 AN: 1000

European-Finnish (FIN) AF: 0.0849 AC: 9 AN: 106

Middle Eastern (MID) AF: 0.0843 AC: 42 AN: 498

European-Non Finnish (NFE) AF: 0.0857 AC: 4566 AN: 53264

Other (OTH) AF: 0.0938 AC: 654 AN: 6974

GnomAD4 genome AF: 0.0867 AC: 13188 AN: 152172 Hom.: 966 Cov.: 32 AF XY: 0.0916 AC XY: 6811 AN XY: 74380

African (AFR) AF: 0.0202 AC: 838 AN: 41550

American (AMR) AF: 0.239 AC: 3650 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3468

East Asian (EAS) AF: 0.0897 AC: 464 AN: 5170

South Asian (SAS) AF: 0.159 AC: 765 AN: 4808

European-Finnish (FIN) AF: 0.105 AC: 1109 AN: 10572

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0856 AC: 5822 AN: 68010

Other (OTH) AF: 0.0905 AC: 191 AN: 2110

Alfa AF: 0.0933 Hom.: 1408

Bravo AF: 0.0952

Asia WGS AF: 0.138 AC: 478 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Three Vessel Coronary Disease Uncertain:1

-

Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3217986; hg19: chr9-22005330;